SE454512B - 7beta-ISOTIAZOLYLTIOACETAMIDO-7alpha-METOXICEFALOSPORANSYRADERIVAT - Google Patents
7beta-ISOTIAZOLYLTIOACETAMIDO-7alpha-METOXICEFALOSPORANSYRADERIVATInfo
- Publication number
- SE454512B SE454512B SE8306298A SE8306298A SE454512B SE 454512 B SE454512 B SE 454512B SE 8306298 A SE8306298 A SE 8306298A SE 8306298 A SE8306298 A SE 8306298A SE 454512 B SE454512 B SE 454512B
- Authority
- SE
- Sweden
- Prior art keywords
- group
- general formula
- methoxy
- compound
- reaction
- Prior art date
Links
- -1 dimethylcarbamoyl group Chemical group 0.000 claims description 49
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229930186147 Cephalosporin Natural products 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 229940124587 cephalosporin Drugs 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 150000001780 cephalosporins Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- GQCBSBCLRPHXEH-UHFFFAOYSA-N 2-(1,2-thiazol-3-yl)ethanethioic s-acid Chemical compound OC(=S)CC=1C=CSN=1 GQCBSBCLRPHXEH-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 125000001113 thiadiazolyl group Chemical class 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000003831 tetrazolyl group Chemical class 0.000 description 3
- IKWLIQXIPRUIDU-ZCFIWIBFSA-N (6r)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound OC(=O)C1=CCS[C@@H]2CC(=O)N12 IKWLIQXIPRUIDU-ZCFIWIBFSA-N 0.000 description 2
- OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- HRWBGLRXDDPRSB-UHFFFAOYSA-N 1,3-dithietane-2-carboxylic acid Chemical compound OC(=O)C1SCS1 HRWBGLRXDDPRSB-UHFFFAOYSA-N 0.000 description 1
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 1
- ADBZITNCVWIJSK-UHFFFAOYSA-N 2-(1,2-thiazol-3-yl)acetamide Chemical group NC(=O)CC=1C=CSN=1 ADBZITNCVWIJSK-UHFFFAOYSA-N 0.000 description 1
- MSMSFIAFGZGBPP-UHFFFAOYSA-N 2-(1,2-thiazol-3-yl)ethanethioamide Chemical group NC(=S)CC=1C=CSN=1 MSMSFIAFGZGBPP-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- ZBVBEDHSKUCFEQ-UHFFFAOYSA-N 3-oxo-1,2-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSN=C1O ZBVBEDHSKUCFEQ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- YFMNGDFZRBMFAI-UHFFFAOYSA-N 4-amino-5-ethylsulfanyl-1,2-thiazol-3-one Chemical compound CCSC=1SN=C(O)C=1N YFMNGDFZRBMFAI-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- BNBWBWVTDHNAMR-UHFFFAOYSA-N 5-ethylsulfanyl-3-oxo-1,2-thiazole-4-carbohydrazide Chemical compound CCSC=1SN=C(O)C=1C(=O)NN BNBWBWVTDHNAMR-UHFFFAOYSA-N 0.000 description 1
- OTWTZCYGNFNPIJ-UHFFFAOYSA-N 5-ethylsulfanyl-3-oxo-1,2-thiazole-4-carboxylic acid Chemical compound CCSC=1SN=C(O)C=1C(O)=O OTWTZCYGNFNPIJ-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- VXVSUNHSNGSNFY-UHFFFAOYSA-N C(C)(=S)OC1=C(C(=NS1)OC)C#N.[K] Chemical compound C(C)(=S)OC1=C(C(=NS1)OC)C#N.[K] VXVSUNHSNGSNFY-UHFFFAOYSA-N 0.000 description 1
- VNYBILMUBZWDAX-UHFFFAOYSA-N C(C)OC(=O)C=1C(=NSC1SCCN)O Chemical compound C(C)OC(=O)C=1C(=NSC1SCCN)O VNYBILMUBZWDAX-UHFFFAOYSA-N 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012021 ethylating agents Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- UHAAFJWANJYDIS-UHFFFAOYSA-N n,n'-diethylmethanediimine Chemical compound CCN=C=NCC UHAAFJWANJYDIS-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- ZUFQCVZBBNZMKD-UHFFFAOYSA-M potassium 2-ethylhexanoate Chemical compound [K+].CCCCC(CC)C([O-])=O ZUFQCVZBBNZMKD-UHFFFAOYSA-M 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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Description
l0 15 20 25 30 35 454 512 2 en metoxigrupp är R2 en cyanogrupp; och R3 representerar en metylgrupp eller en hydroximetyl- 9fUPPi eller ett farmaceutiskt acceptabelt salt därav. a methoxy group, R 2 is a cyano group; and R 3 represents a methyl group or a hydroxymethyl-9fUPPi or a pharmaceutically acceptable salt thereof.
Under de senaste årtiondena har olika antibiotika undersökts och använts för behandling av olika infek- tionssjukdomar hos djur inklusive människor men eftersom resistenta bakterier förekommer i många fall finns det vissa infektionssjukdomar, som ej har behandlats med kända antibiotika.In recent decades, various antibiotics have been investigated and used to treat various infectious diseases in animals, including humans, but since resistant bacteria are present in many cases, there are certain infectious diseases which have not been treated with known antibiotics.
Vidare söker man ständigt efter nya antibiotika för att komplettera och utvidga läkarnas utrustning särskilt för behandling av infektioner, som inbegriper patogena organismer, som har blivit resistenta mot så- dana kemoterapeutiska medel, som nu användes.Furthermore, new antibiotics are constantly being sought to supplement and expand physicians' equipment, especially for the treatment of infections, including pathogenic organisms that have become resistant to such chemotherapeutic agents, which are now in use.
Olika cefalosporiner är kända och ett flertal skrifter, såsom DE OS 2 356 388 beskriver ett flertal cefalosporiner eller heterocykliska acylgrupper mycket vittomfattande, men ingen av dessa skrifter specificerar föreningarna enligt föreliggande uppfinning.Various cephalosporins are known and a number of publications, such as DE OS 2 356 388 describe a number of cephalosporins or heterocyclic acyl groups very broadly, but none of these publications specify the compounds of the present invention.
I SE patentskriften 438 338 beskrivs nya cefalospo- riner, som kan åskådliggöras med den allmänna formeln (I) ?cH3 S RJK /s ' Rv = \S>- com: __- f N / cH2s-n3 I 0 COOH lO 15 20 25 30 35 454 512 3 vari Rl betecknar en karboxylgrupp, en lågalkoxikarbonyl- grupp, en cyanogrupp, en karbamoylgrupp eller en mono- eller di-làgalkylkarbamoylgrupp; R2 betecknar en väte- atom, en làgalkylgrupp, eventuellt substituerad med en karboxylgrupp eller en hydroxylgrupp, en làgalkoxi- grupp, R4S(0)n-grupp (vari R4 betecknar en làgalkylgrupp och n betecknar 0, l eller 2), en lågalkanoylgrupp, en fenylgrupp eventuellt substituerad med en hydroxi- grupp, en bensoylgrupp, en karboxylgrupp, en lågalkoxi- karbonylgrupp eventuellt substituerad med en hydroxi- grupp eller en karboxylgrupp, en cyanogrupp, en karb- amoylgrupp, en mono- eller di-làgalkylgrupp, en låg- alkenylgrupp, en sulfamoylgrupp, en pyridinylgrupp eller en tfifiiazolylgrupp eventuellt substituerad med en låg- alkyltiogrupp; R3 betecknar en làgalkyl-substituerad tetrazolylgrupp eller en làgalkyl-substituerad tiadi- azolylgrupp, samt farmaceutiskt godtagbara salter därav.SE patent specification 438 338 describes new cephalosporins which can be illustrated by the general formula (I)? CH3 S RJK / s' Rv = \ S> - com: __- f N / cH2s-n3 I 0 COOH 10 Wherein R 1 represents a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a carbamoyl group or a mono- or di-lower alkylcarbamoyl group; R 2 represents a hydrogen atom, a lower alkyl group, optionally substituted by a carboxyl group or a hydroxyl group, a lower alkoxy group, R 4S (O) n group (wherein R 4 represents a lower alkyl group and n represents 0, 1 or 2), a lower alkanoyl group, a phenyl group optionally substituted with a hydroxy group, a benzoyl group, a carboxyl group, a lower alkoxycarbonyl group optionally substituted with a hydroxy group or a carboxyl group, a cyano group, a carbamoyl group, a mono- or di-lower alkyl group, a lower an alkenyl group, a sulfamoyl group, a pyridinyl group or a thiazolyl group optionally substituted by a lower alkylthio group; R 3 represents a lower alkyl-substituted tetrazolyl group or a lower alkyl-substituted thiadiazolyl group, and pharmaceutically acceptable salts thereof.
Dessa cefalosporinföreningar har utomordentligt god antibakteriell verkan, särskilt mot gram-negativa bakterier.These cephalosporin compounds have extremely good antibacterial activity, especially against gram-negative bacteria.
Lågalkylgruppen i den allmänna formeln kan utgöras av en rak eller grenad alkylgrupp med l-4 kolatomer, såsom metyl, etyl, isopropyl, n-butyl, tert-butyl etc.The lower alkyl group in the general formula may be a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, isopropyl, n-butyl, tert-butyl, etc.
R3 i den allmänna formeln I betecknar såsom an- givits ovan en lågalkyl-substituerad tetrazolylgrupp eller en lågalkyl-substituerad tiadiazolylgrupp, och exempel på tetrazolylgruppen är en lH-tetrazol-5-yl- -grupp, 2H-tetrazol-5-yl-grupp, etc och exempel på tiadiazolylgruppen är en l,3,4-tiadiazolylgrupp, en l,2,5-tiadiazolylgrupp, en l,2,4-tiadiazolylgrupp, etc.R 3 in the general formula I represents as indicated above a lower alkyl-substituted tetrazolyl group or a lower alkyl-substituted thiadiazolyl group, and examples of the tetrazolyl group are a 1H-tetrazol-5-yl group, 2H-tetrazol-5-yl group , etc. and examples of the thiadiazolyl group are a 1,3,4-thiadiazolyl group, a 1,2,5-thiadiazolyl group, a 1,2,4-thiadiazolyl group, etc.
De grupper och rester, som betecknas med Rl, R2, R3 och R4 substituerade då de har substituenter. Exempel på sub- i den allmänna formeln I, kan vidare vara stituerade grupper eller rester är en N-monoalkylkarb- amoylgrupp, en N-dialkylkarbamoylgrupp och en alkoxi- karbonylaminogrupp för Rl, en hydroxialkylgrupp, en karboxialkylgrupp, en alkoxialkylgrupp, en arylalkyl- l0 15 20 25 30 4454 5'I2 4 grupp, en hydroxifenylgrupp och en alkoxifenylgrupp för R2 och en alkyltio-substituerad tiadiazolylgrupp för R3, etc.The groups and residues designated by R 1, R 2, R 3 and R 4 are substituted when they have substituents. Examples of sub- in the general formula I, may further be substituted groups or residues are an N-monoalkylcarbamoyl group, an N-dialkylcarbamoyl group and an alkoxycarbonylamino group for R1, a hydroxyalkyl group, a carboxyalkyl group, an alkoxyalkyl group, an arylalkyl-10 4454 5'I2 4 group, a hydroxyphenyl group and an alkoxyphenyl group for R 2 and an alkylthio-substituted thiadiazolyl group for R 3, etc.
Det mest utmärkande draget för föreningarna med den allmänna formeln I är att acylgruppen i 7ß-ställning frambringar en 4-substituerad metylen-l,3-ditietan-2- -karboxylsyra. Acylering med karboxylsyra med 4-ledad ring har hittills ej varit känd inom cefalosporinkemi- området och särskilt mà nämnas att l,3-ditietankarb- oxylsyran som sådan, som användes i en av metoderna för framställning av föreningarna, är en ny förening, som ej beskrives i någon litteratur.The most distinctive feature of the compounds of general formula I is that the acyl group in the 7β-position produces a 4-substituted methylene-1,3-dithietane-2-carboxylic acid. Acylation with carboxylic acid with 4-membered ring has not hitherto been known in the field of cephalosporin chemistry, and it is especially worth mentioning that the 1,3-dithietanecarboxylic acid as such, which is used in one of the methods for the preparation of the compounds, is a novel compound which is not described in any literature.
Föreningarna med formeln (I) kan framställas enligt _följande metoder: Metod l: Enligt denna metod framställes föreningen med den allmänna formeln I genom att den 4-substituerade mety- len-l,3-ditietankarboxylsyra, som åskàdliggöres med den allmänna formeln (II) l R S \ / ï: COOH II 122 Z \s : vari Rl och R2 har samma betydelse som i den allmänna formeln I, bringas att reagera med 7ß-amino-7a-metoxi- -3-heterocyklisk tiometyl-A3-cefem-4-karboxylsyra, som åskådliggöres med den allmänna formeln III QCH3 S H2N"_'__]// 111 af "_ ,/' cnz-s-R3 COOH 10 15 20 25 30 4154 5'12 vari R3 har samma betydelse som i den allmänna formeln I.The compounds of formula (I) may be prepared according to the following methods: Method 1: According to this method the compound of general formula I is prepared by substituting the 4-substituted methylene-1,3-dithietanecarboxylic acid which is illustrated by the general formula (II) wherein R 1 and R 2 have the same meaning as in the general formula I, are reacted with 7β-amino-7α-methoxy-3-heterocyclic thiomethyl-A3-cephem-4 carboxylic acid, which is illustrated by the general formula III QCH 3 S H 2 N "_'__] // 111 af" _, / 'cnz-s-R3 COOH 10 15 20 25 30 4154 5'12 wherein R 3 has the same meaning as in the general formula I.
Vid reaktionen mellan föreningen med den allmänna formeln II och föreningen med den allmänna formeln III kan föreningarna bringas reagera direkt med varandra i närvaro av ett kondensationsmedel, såsom N,N'-dicyklo- hexylkarbodiimid etc, men det är lämpligt att använda en förening med formeln II efter det att man infört kända 1 och R2 alltefter egenskaperna hos skyddsgrupper för R Rl och R2 och även föreningen med formeln III efter in- förande av en känd skyddsgrupp för karboxylgruppen i 4-stä11ning. nå Rl och/eller az i föreningen mea førmein II exempelvis betecknar en karboxylgrupp skyddas före- ningens karboxylgrupp och också karboxylgruppen i 4-ställ- ning i föreningen med formeln III i förväg genom en tri- fenylmetylgrupp, en tert-butylgrupp, en benshydrylgrupp etc, och vidare överföres karboxylsyran i 2-ställning av föreningen med formeln II eller aminogruppen i 7B- -ställning i föreningen med formeln III till reaktions- benägna derivat innan reaktionen genomföres. Lämpliga exempel på reaktionsbenägna derivat av karboxylsyran är en syrahalogenid, en blandad syraanhydrid, en aktiv ester, en aktiv amid, en syraanhydrid, en syraazid etc.In the reaction between the compound of general formula II and the compound of general formula III, the compounds may be reacted directly with each other in the presence of a condensing agent, such as N, N'-dicyclohexylcarbodiimide, etc., but it is convenient to use a compound of formula II after the introduction of known 1 and R2 according to the properties of protecting groups for R1, R1 and R2 and also the compound of formula III after the introduction of a known protecting group for the carboxyl group in the 4-position. reaching R1 and / or az in the compound mea form II for example denotes a carboxyl group, the carboxyl group of the compound and also the carboxyl group in the 4-position in the compound of formula III are protected in advance by a triphenylmethyl group, a tert-butyl group, a benzhydryl group etc. , and further, the carboxylic acid in the 2-position of the compound of formula II or the amino group in the 7B-position of the compound of the formula III is converted into reaction-prone derivatives before the reaction is carried out. Suitable examples of reaction-prone derivatives of the carboxylic acid are an acid halide, a mixed acid anhydride, an active ester, an active amide, an acid anhydride, an acid azide, etc.
Föreningarna med den allmänna formeln II är nya föreningar och de erhålles genom att en 2,2'-substi- turerad etylen-l,l-ditiol med den allmänna formeln IV H2/ _ \sH vari Rl och R2 har samma betydelse som i den allmänna formeln I bringas att reagera med en dihalogenättik- syra eller en lågalkylester därav, som åskådliggöres med den allmänna formeln V 10 l5 20 25 30 454 512 X 7 >cH-coø1a v x vari X betecknar en halogenatom, och R7 betecknar en väteatom eller en lågalkylgrupp, och då föreningen med formeln V utgöres av lågalkylestern frigöres därefter alkylen eller överföres till ett reaktionsbenäget deri- vat.The compounds of the general formula II are new compounds and they are obtained by a 2,2'-substituted ethylene-1,1-dithiol of the general formula IV H2 / _ \ sH wherein R1 and R2 have the same meaning as in the the general formula I is reacted with a dihaloacetic acid or a lower alkyl ester thereof, which is illustrated by the general formula V 10 l 5 20 25 30 454 512 X 7> cH-carbon vx wherein X represents a halogen atom, and R 7 represents a hydrogen atom or a lower alkyl group, and when the compound of formula V is the lower alkyl ester, the alkylene is then liberated or converted to a reaction-derivative.
Reaktionen mellan föreningeumed formel II och föreningen med formeln III eller det reaktionsbenägna derivatet därav genomföres vanligen i ett inert lös- ningsmedel under uppvärmning eller kylning men för att undvika epimerisering av metoxigruppen i 7a-ställning under reaktionen är det lämpligt att man genomför reak- tionen vid låg temperatur, särskilt vid temperaturer under -20°C.The reaction between compound of formula II and the compound of formula III or the reaction-prone derivative thereof is usually carried out in an inert solvent under heating or cooling, but in order to avoid epimerization of the methoxy group in the 7a position during the reaction, it is convenient to carry out the reaction at low temperature, especially at temperatures below -20 ° C.
Den på detta sätt bildade föreningen kan överföras till föreningen med formel I genom att skyddsgruppen eller skyddsgrupperna avlägsnas på vanligt sätt.The compound thus formed can be transferred to the compound of formula I by removing the protecting group or groups in the usual manner.
Metod 2: I denna metod framställes föreningen med den all- männa formeln I genom att man bringar 3-acetoximetyl- eller 3-karbamoyloximetyl-7B-(4-substituerad-l,3-di- tietankarboxamido)-7d-metoxi-A3-cefem-4-karboxylsyra med den allmänna formeln VI ocn RK /S> E 3 /S 2/,==\\S CONH-- VI R --N cH H6 á / 20 10 15 20 25 30 'formeln I och R 454 512 vari Rl och R2 har samma betydelse som i den allmänna 6 betecknar en acetylgrupp eller en karbamoylgrupp, att reagera med den heterocykliska tiol, som kan åskådliggöras med den allmänna formeln VII R3 - SH VII vari R3 har samma betydelse som i den allmänna formeln I eller ett alkalimetallsubstitut därav vid merkaptogruppens väteatom.Method 2: In this method, the compound of general formula I is prepared by substituting 3-acetoxymethyl- or 3-carbamoyloxymethyl-7B- (4-substituted-1,3-diethietanecarboxamido) -7d-methoxy-A3- cephem-4-carboxylic acid of the general formula VI and RK / S> E 3 / S 2 /, == \\ S CONH-- VI R --N cH H6 á / 20 10 15 20 25 30 'formula I and R 454 512 wherein R1 and R2 have the same meaning as in the general 6 denote an acetyl group or a carbamoyl group, to react with the heterocyclic thiol, which can be illustrated by the general formula VII R3 - SH VII wherein R3 has the same meaning as in the general formula I or an alkali metal substitute thereof at the hydrogen atom of the mercapto group.
Reaktionen genomföres vid rumstemperatur eller under uppvärmningen, vanligen i ett inert lösningsmedel.The reaction is carried out at room temperature or during heating, usually in an inert solvent.
Exempel på inerta lösningsmedel är aceton, dimetylform- amid, metanol, etanol, vatten och ett fosfatbuffert- medel och, om nödvändigt, användes de såsom en blandning av dem. Då föreningen med den allmänna formeln VII an- vändes i fritt tillstånd är det lämpligt att man genomför reaktionen i närvaro av en bas, såsom alkalimetall- hydroxid, alkalimetallkarbonat, alkalimetallvätekarbo- nat, trialkylamin, pyridin, dimetylanilin, etc. Efter avslutad reaktion isoleras föreningen med formeln I genom att reaktionsblandningen surgöres och de på detta sätt bildade utfällningarna utvinnes eller genom att reaktions- blandningen extraheras med lösningsmedel.Examples of inert solvents are acetone, dimethylformamide, methanol, ethanol, water and a phosphate buffer and, if necessary, they are used as a mixture of them. When the compound of general formula VII is used in the free state, it is convenient to carry out the reaction in the presence of a base, such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, trialkylamine, pyridine, dimethylaniline, etc. After completion of the reaction, the compound is isolated of formula I by acidifying the reaction mixture and the precipitates thus formed are recovered or by extracting the reaction mixture with solvent.
Därtill kan föreningen med formeln VI, vilken före- ning användes i denna metod, erhållas genom att man bringar en förening med den allmänna formeln II, som an- vändes i Metod 1, att reagera med 76-amino-7u-metoxi- cefalosporansyra (R6 i formeln betecknar en acetylgrupp) eller 7ß-amino-3-karbamoyloximetyl-7a-metoxi-A3-cefem- '4'karb0XY1SYra (R6 i formeln betecknar -CONH2) med den allmänna formeln VIII 454 512 . 3 s 5 H2N----]/ v11: //_'N / 0112036 COOH 10 vari R6 har samma betydelse som i den allmänna formeln VI under liknande reaktionsbetingelser som i Metod 1_ Metod 3: Den förening som visas med den allmänna formeln l5 I, kan också erhållas genom att man behandlar det 7a-metoxi-3-heterocyklíska tiometylcefalosporin- derivat, som åskådliggöres med formeln IX 20 2 0% CH3 RS/IKS sc1a2coNn-_-|/S IX --V 3 f / c sn zs 0/ H2 .-.O COOH 30 vari R2 och R3 har sama betydelse som i den allmänna formeln I och R8 betecknar en väteatom eller en substi- turerad eller osubstituerad alkylgrupp, under basiska betingelser. 10 15 20 25 30 35 454 512 9 Då vidare RB i den allmänna formeln IX betecknar väte inbegriper derivatet av formeln tautomeren med följande formel IX' IX' vari R2 och R3 har tidigare angivna betydelser.In addition, the compound of formula VI, which compound is used in this method, can be obtained by reacting a compound of the general formula II used in Method 1 with 76-amino-7u-methoxycephalosporanic acid ( R6 in the formula represents an acetyl group) or 7β-amino-3-carbamoyloxymethyl-7α-methoxy-33-cephem- '4'carboxylic acid (R6 in the formula represents -CONH2) of the general formula VIII 454 512. H 2 N ----] / v11: // _ 'N / 0112036 COOH 10 wherein R 6 has the same meaning as in the general formula VI under similar reaction conditions as in Method 1_ Method 3: The compound represented by the general formula 15 I, can also be obtained by treating the 7α-methoxy-3-heterocyclic thiomethylcephalosporin derivative, which is illustrated by the formula IX 20 2 0% CH 3 RS / IKS sc1a2coNn -_- | / S IX --V 3 f / c CO 2 wherein R 2 and R 3 have the same meaning as in the general formula I and R 8 represents a hydrogen atom or a substituted or unsubstituted alkyl group, under basic conditions. Furthermore, when RB in the general formula IX denotes hydrogen, the derivative of the formula includes the tautomer of the following formula IX 'IX' wherein R 2 and R 3 have previously defined meanings.
Lämpliga baser,som användes vid denna metod, är svaga baser, såsom natriumvätekarbonat, kaliumväte~ karbonat, natriumkarbonat, etc. Reaktionen genomföres vanligen med lösningsmedel vid rumstemperatur eller under kylning. Vilket som helst lösningsmedel, som ej påverkar reaktionen, kan användas men man föredrar vatten eller ett organiskt lösningsmedel, som är bland- bart med vatten, såsom metanol, aceton, tetrahydrofuran, dimetylformamid, etc, vilka användes ensamma eller såsom blandningar. Isolering och rening av produkten ur reak- tionsblandningen genomföres på konventionellt sätt, såsom genom extraktion med organiskt lösningsmedel, genom kristallisation, kolonnkromatografi, etc.Suitable bases used in this method are weak bases, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, etc. The reaction is usually carried out with solvent at room temperature or under cooling. Any solvent which does not affect the reaction may be used, but water or an organic solvent which is miscible with water, such as methanol, acetone, tetrahydrofuran, dimethylformamide, etc., which are used alone or as mixtures, is preferred. Isolation and purification of the product from the reaction mixture are carried out in a conventional manner, such as by extraction with organic solvent, by crystallization, column chromatography, etc.
Den förening med den allmänna formeln IX, som an- vändes i metoden, har själv utomordentlig antibakteriell verkan liksom den är användbar såsom mellanprodukt för föreningen med formeln I. Ändamålet med uppfinningen är därför att anvisa en mellanprodukt, som har utomordentlig antibakteriell verkan och är lämplig för framställning av föreningen med formeln I.The compound of general formula IX used in the method itself has excellent antibacterial activity as well as being useful as an intermediate for the compound of formula I. The object of the invention is therefore to provide an intermediate which has excellent antibacterial activity and is suitable for the preparation of the compound of formula I.
Mellanprodukten med den allmänna formeln IX fram- ställes exempelvis enligt följande metoder: 10 15 20 25 30 35 454 512 l0 Metod A: Föreningen med den allmänna formeln III kan bringas reagera med en motsvarande isotiazolyltioättíksyra eller ett reaktionsbenäget derivat därav enligt Metod l i upp- finningen. Detta innebär att reaktionen vanligen genom- föres i ett inert lösningsmedel, såsom företrädesvis aceton, kloroform, metylenklorid, etylenklorid, tetra- hydrofuran, dimetylformamid, acetonitril, etylacetat, etylformiat, etc. Dessa lösningsmedel kan användas en- samna eller i kombinationer eller, om lösningsmedlet är vattenlösligt, kan lösningsmedlet användas såsom en bland- ning med vatten om inga hinder inträffar i reaktionen.The intermediate of general formula IX is prepared, for example, according to the following methods: Method A: The compound of general formula III can be reacted with a corresponding isothiazolylthioacetic acid or a reaction-prone derivative thereof according to Method I of the invention. . This means that the reaction is usually carried out in an inert solvent, such as preferably acetone, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, ethyl acetate, ethyl formate, etc. These solvents may be used alone or in combinations or, if the solvent is water soluble, the solvent can be used as a mixture with water if no obstacles occur in the reaction.
Föredragna exempel på reaktionsbenägna derivat vid isotiazolyktioättiksyrans terminala karboxylgrupp är en syrahalogenid, en blandad syraanhvdrid, en aktiv ester, en aktiv amid, en syraanhydrid, en syraazid etc. Då den terminala karboxylgruppen utgöres av fri radikal är det lämpligt att använda ett kondenserade medel, såsom N,N'-dicyklohexylkarbodiimid, N,N'-dietylkarbodiimid, etc.Preferred examples of reaction-prone derivatives at the terminal carboxyl group of the isothiazolyctioacetic acid are an acid halide, a mixed acid anhydride, an active ester, an active amide, an acid anhydride, an acid azide, etc. When the terminal carboxyl group is free radical, it is convenient to use a condensed agent. N, N'-dicyclohexylcarbodiimide, N, N'-diethylcarbodiimide, etc.
Då vidare R2 i isotiazolyltioättiksyran utgöres av en reaktionsbenägen grupp, som kan hindra reaktionen, såsom en karboxylgrupp, hydroximetylgrupp, etc, är det lämpligt att använda isotiazolyltioättiksyran i reaktionen efter det att man infört en konventionell skyddsgrupp för den reaktionsbenägna gruppen. I detta fall är det lämpligt att frigöra skyddsgruppen efter det att man erhållit föreningen med formeln IX, eller efter det att föreningen med formeln IX Överförd till föreningen med formel I.Furthermore, since R2 in the isothiazolylthioacetic acid is a reaction-prone group which can inhibit the reaction, such as a carboxyl group, hydroxymethyl group, etc., it is convenient to use the isothiazolylthioacetic acid in the reaction after introducing a conventional protecting group for the reaction-prone group. In this case, it is appropriate to release the protecting group after obtaining the compound of formula IX, or after the compound of formula IX has been transferred to the compound of formula I.
Metod B: Föreningen med den allmänna formeln IX kan också erhållas genom att man bringar att reagera den förening, som visas med den allmänna formeln VIII och motsvarande isotiazolyltioättíksyra eller reaktionsbenägna derivat därav och sedan bringa: produkten att reagera med den förening, som visas med den allmänna formeln VIII enligt metod 2. f) 10 15 20 25 30 35 454 512 ll Metod C: Föreningen med den allmänna formeln IX erhålles vidare genom att man bringar att reagera den kända 7a-amino-7B-haloacetamido-3-heterocykliska tiometyl-A3- ~cefem-4-karboxylsyra, såsom visas med den allmänna formeln X ?CH3 X-cnzcomx -'-|/ S x //"_N / cH2s-R3 0 COOH vari R3 har samma betydelse som ovan och X betecknar en halogenatom, och den förening, som visas med den allmän- na formeln XI 2 O R \ \ XI ef" n \s sn vari R2 och R3 har samma betydelse som ovan och R8 be- tecknar en väteatom eller en substituerad eller osub- stituterad alkylgrupp, under basiska betingelser.Method B: The compound of general formula IX can also be obtained by reacting the compound represented by the general formula VIII and the corresponding isothiazolylthioacetic acid or reactive derivatives thereof and then reacting the product with the compound represented by the general formula VIII according to method 2. f) 10 C 205 Method 454 512 II Method C: The compound of general formula IX is further obtained by reacting the known 7α-amino-7β-haloacetamido-3-heterocyclic thiomethyl- A3--cephem-4-carboxylic acid, as represented by the general formula X? CH3 X-cnzcomx -'- | / S x // "_ N / cH2s-R3 COOH wherein R3 has the same meaning as above and X represents a halogen atom , and the compound represented by the general formula XI 2 OR \ \ XI ef "n \ s sn wherein R 2 and R 3 have the same meaning as above and R 8 represents a hydrogen atom or a substituted or unsubstituted alkyl group, under basic conditions.
Då vidare R8 i den allmänna formeln XI betecknar en väteatom inbegriper föreningen med formeln XI den tautomer därav, som visas med följande formel XI' no Rz I I XI' N \s SH vari R2 har samma betydelse som ovan. 10 15 20 25 454 512 12 Reaktionen genomföres vanligen i ett lösningsmedel vid rumstemperatur eller under kylning. Vilket som helst lösningsmedel, som ej deltar i reaktionen, kan användas utan begränsningar, men vanligen användes vatten, metanol, aceton, tetrahydrofuran, dimetylformamid eller en blandning därav, såsom lösningsmedel. Föreningen med for- meln XI kan vanligen användas såsom alkalimetallsaltet därav vid merkaptogruppen men då föreningen med formeln XI användes som sådan genomföres reaktionen i närvaro av en alifatisk, aromatisk eller heterocyklisk bas, såsom trietylamin, N,N-dimetylanilin, N-etylmorfolin, pyridin, kollidin, 2,6-lutidin, etc eller ett alkalimetallkarbo- nat eller alkalimetallvätekarbonat, såsom natriumkarbonat, kaliumkarbonat, natriumvätekarbonat, kaliumvätekarbonat, etc.Furthermore, when R8 in the general formula XI represents a hydrogen atom, the compound of the formula XI includes the tautomer thereof, which is represented by the following formula XI 'no Rz I I XI' N \ s SH wherein R2 has the same meaning as above. The reaction is usually carried out in a solvent at room temperature or under cooling. Any solvent which does not participate in the reaction can be used without limitation, but usually water, methanol, acetone, tetrahydrofuran, dimethylformamide or a mixture thereof are used as solvent. The compound of formula XI can usually be used as the alkali metal salt thereof in the mercapto group, but when the compound of formula XI is used as such, the reaction is carried out in the presence of an aliphatic, aromatic or heterocyclic base such as triethylamine, N, N-dimethylaniline, N-ethylmorpholine, pyridine , collidine, 2,6-lutidine, etc. or an alkali metal carbonate or alkali metal bicarbonate such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.
Föreningarna med den allmänna formeln IX, som erhål- les på detta sätt, är nya föreningar. De föreningar, som har en isotiazolylacetamidgrupp i 7-ställning är kända inom cefalosporinkemin såsom visas i exempelvis US PS 3 464 999, men de föreningar, som har en isotia- zolyltioacetamídgrupp, som kan överföras till en l,3-di- tietankarboxamidgrupp har ej ännu beskrivits.The compounds of the general formula IX obtained in this way are new compounds. The compounds having an isothiazolylacetamide group in the 7-position are known in cephalosporin chemistry as shown in, for example, U.S. Pat. No. 3,464,999, but those compounds having an isothiazolylthioacetamide group which can be converted to a 1,3-diethietanecarboxamide group do not have yet described.
Föreningar med formeln I uppvisar utomordentlig antibakteriell verkan, särskilt mot gram-negativa bak- terier, såsom visas i det följande. 13 TABELL* -u/Lïpc. ^) ' 'tv/mn Klebsiella Proteus 454 Proteus 512 Escherichia pneumoniae vulgaris morganii Seratia Exempel nr. Coli NIHJ' ATCC 10031 OXK US Kono marcenscens 1 0,2 0,2 1,56 1,56 3,13 2 0,78 1,56 3,13 12,5 6,25 4 0,78 0,78 3,13 6,24 6,25 5 0,09 0,09 0,78 1,56 0,78 6 0,09 0,09 0,39 0,78 0,39 7 0,78 0,39 0,78 6,25 6,25 8 0,09 0,09 0,39 0,39 0,39 9 0,19 0,39 0,78 0,78 ll 0,19 0,19 1,56 0,39 0,39 12 0,78 0,39 0,78 14 0,19 0,19 1,56 1,56 0,78 15 0,19 0,19 1,56 3,13 0,78 16 0,39 0,39 0,78 6,25 6,25 17 0,39 0,39 0,78 0,39 12,5 18 0,78 0,78 3,13 19 0,19 0,09 0,78 0,39 1,56 22 0,78 0,39 0,78 3,13 3,13 23 1,56 1,56 1,56 6,25 6,25 24 0,39 0,39 0,78 3,13 0,78 25 0,19 0,09 0,78 0,39 0,39 26 0,78 0,39 1,56 1,56 0,78 29 0,78 0,78 1,56 6,25 1,56 30 0,09 0,20 0,78 32 i 0,20 0,20 0,78 0,78 0,39 lO 15 20 25 30 35 454 512 J 14 Föreningarna med formeln T kan lätt omvandlas till w farmaceutiskt godtagbara icke-toxiska eller verksamma salter därav. Dessa salter inbegriper alkalimetallsalter, såsom natrium- eller kaliumsalt eller -salter (t ex med natrium- eller kalium-2-etyl-hexanoat), ammoniumsalt 'r eller -salter och organiskt aminsalt eller -salter, så- som sâdana salter, som erhålles med prokain eller etanol- amin, som kan framställas av fackmannen på känt sätt.Compounds of formula I show excellent antibacterial activity, especially against gram-negative bacteria, as shown below. 13 TABLE * -u / Lïpc. ^) '' tv / mn Klebsiella Proteus 454 Proteus 512 Escherichia pneumoniae vulgaris morganii Seratia Example no. Coli NIHJ 'ATCC 10031 OXK US Kono marcenscens 1 0.2 0.2 1.56 1.56 3.13 2 0.78 1.56 3.13 12.5 6.25 4 0.78 0.78 3, 13 6.24 6.25 5 0.09 0.09 0.78 1.56 0.78 6 0.09 0.09 0.39 0.78 0.39 7 0.78 0.79 0.78 6 .25 6.25 8 0.09 0.09 0.39 0.39 0.39 9 0.19 0.39 0.78 0.78 ll 0.19 0.19 1.56 0.39 0.39 12 0.78 0.39 0.78 14 0.19 0.19 1.56 1.56 0.78 15 0.19 0.19 1.56 3.13 0.78 16 0.39 0.39 0 .78 6.25 6.25 17 0.39 0.39 0.78 0.39 12.5 18 0.78 0.78 3.13 19 0.19 0.09 0.78 0.39 1.56 22 0.78 0.79 0.78 3.13 3.13 23 1.56 1.56 1.56 6.25 6.25 24 0.39 0.39 0.78 3.13 0.78 25 0 .19 0.09 0.78 0.39 0.39 26 0.78 0.39 1.56 1.56 0.78 29 0.78 0.78 1.56 6.25 1.56 30 0.09 0.20 0.78 32 i 0.20 0.20 0.78 0.78 0.39 10 15 The compounds of formula T can be readily converted into pharmaceutically acceptable non-toxic or active salts. hence. These salts include alkali metal salts, such as sodium or potassium salt or salts (eg with sodium or potassium 2-ethyl hexanoate), ammonium salts or salts and organic amine salt or salts, such as salts obtained with procaine or ethanolamine, which can be prepared by those skilled in the art in a known manner.
Föreningarna med formeln I kan administreras oralt, rektalt, genom injektion, såsom subkutant, intramuskulärt eller intravenöst.The compounds of formula I may be administered orally, rectally, by injection, such as subcutaneously, intramuscularly or intravenously.
En injektion av pà lämpligt sätt framställda sterila lösningar eller suspensioner, som innehåller en verksam men icke toxisk mängd av cefalosporinföre- ningen med formeln I, är det föredragna administra- tionssättet.An injection of suitably prepared sterile solutions or suspensions containing an effective but non-toxic amount of the cephalosporin compound of formula I is the preferred mode of administration.
Dosen av cefalosporinföreningen uppgår van- ligen till 250-3000 mg/dag för en vuxen individ och den kan varieras på olika sätt allt efter sjukdoms- tillståndet, åldern, vikt och tillstånd hos patienten.The dose of the cephalosporin compound is usually 250-3000 mg / day for an adult individual and it can be varied in different ways depending on the disease state, age, weight and condition of the patient.
Uppfinningen kommer att ytterligare beskrivas mera detaljerat under hänvisning till följande exempel.The invention will be further described in more detail with reference to the following examples.
EXEMPEL l I 10 ml flytande ammoniak suspenderades 270 mg 4-karboxi-5-etyltio-3-hydroxiisotiazol. Efter det att suspensionen kylts till -50°C och man tillsatt 100 mg metalliskt natrium omrördes blandningen i 30 min vid temperatur från -SOOC till -33°C.EXAMPLE 1 In 10 ml of liquid ammonia was suspended 270 mg of 4-carboxy-5-ethylthio-3-hydroxyisothiazole. After the suspension was cooled to -50 ° C and 100 mg of metallic sodium was added, the mixture was stirred for 30 minutes at a temperature from -SOOC to -33 ° C.
Den flytande ammoniaken avdestillerades från reak- tionsblandningen, den återstod, som erhölls därvid, löstes i 20 ml metanol, varefter lO ml metanollösning av 600 mg 7B-bromacetamido-7a-metoxi-3-(l-metyltetrazol-5-yl)tio- metyl-A3-cefem-4-karboxylsyra droppvis tillsattes till lös- u ningen under kylning med is och efter det att blandningen omrörts i 30 min under iskylning omrördes blandningen i ytterligare 30 min vid rumstemperatur. Efter avslutad reaktion inställdes reaktionsblandningens pH på 4 med 4n 1 10 15 20 25 30 454 512 15 saltsyra och reaktionslösningsmedlet avdestillerades under förminskat tryck.The liquid ammonia was distilled off from the reaction mixture, the residue thus obtained was dissolved in 20 ml of methanol, then 10 ml of methanol solution of 600 mg of 7B-bromoacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) thio- methyl 3 3 -cephem-4-carboxylic acid was added dropwise to the solution under ice-cooling, and after the mixture was stirred for 30 minutes under ice-cooling, the mixture was stirred for a further 30 minutes at room temperature. After completion of the reaction, the pH of the reaction mixture was adjusted to 4 with 4N hydrochloric acid and the reaction solvent was distilled off under reduced pressure.
Den bildade återstoden försattes med vatten och efter det att blandningens pH inställts på l med 4n saltsyra extraherades produkten med 50 ml av en blandning av buta- nol och etylacetat (volymförhällande 1:1). Det bildade organiska skiktet tvättades 2 ggr med vatten och därefter l gång med mättad vattenhaltig natriumkloridlösning, torkades över vattenfritt magnesiumsulfat och därefter avdestillerades lösningsmedlet under förminskat tryck. Återstoden försattes med 30 ml i eter och de bildade fällningarna utvanns genom filtrering, tvättades 3 ggr med 20 ml eter och torkades under förminskat tryck, var- vid man erhöll 560 mg pulver av 7B-(4-karboxi-3-hydroxi- isotiazol-5-yl)tioacetamido-7a-metoxi~3-(1-metyltetrazol~ -5-yl)tiometyl-A3-cefem-4-karboxylsyra.The residue formed was added with water, and after adjusting the pH of the mixture to 1N with 4N hydrochloric acid, the product was extracted with 50 ml of a mixture of butanol and ethyl acetate (1: 1 by volume). The formed organic layer was washed twice with water and then once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was added with 30 ml of ether and the precipitates formed were recovered by filtration, washed 3 times with 20 ml of ether and dried under reduced pressure to give 560 mg of a powder of 7B- (4-carboxy-3-hydroxyisothiazole). 5-yl) thioacetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-33-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO) 6 (ppm)= 3,41 (3H), 3,58 (za), 3,93 (sn), 3,99 (zu) 4,28 (2H), 5,10 (lH).NMR Spectrum (D 6 -DMSO) δ (ppm) = 3.41 (3H), 3.58 (za), 3.93 (sn), 3.99 (zu) 4.28 (2H), 5.10 (1H).
EXEMPEL 2 -sou conH-~“*' ___ S 2 ii ä ¿9_~_-N ,// -cH2s- N,N o I coon cnš Efter det att man kylt 40 ml flytande ammoniak till -70°C tillsattes 183 mg 4~amino-5-etyltio-3-hydroxiiso- tiazol, och därefter tillsattes 55 mg natrium till den 10 15 20 25 30 35 454 512 16 flytande ammoniaken. Blandningen omrördes i 10 min vid samma temperatur och därefter avdestillerades flytande amoniak. Återstoden försattes med 15 ml metanol, var- efter man kylde till 2°C. 15 ml av en metanollösning av 300 mg 7ß-bromacetamid-7a-metoxi-3-(l-metyltetrazol-5-yl)- tiometyl-A3-cefem-4-karboxylsyra tillsattes droppvis till blandningen under en period på 30 s, varefter man omrörde i 10 min vid samma temperatur. Lösningsmedlet avdestillerades under förminskat tryck och efter till- sats av 15 ml vatten till återstoden inställdes bland- ningens pH på 2,5 genom tillsats av 5 %-ig saltsyra. De bildade utfällningarna extraherades med 100 ml av en blandning av n-butanol och etylacetat (volymförhållande lzl) och extraktet tvättades med vatten och sedan med en mättad vattenhaltig natriumkloridlösning och torkades över vattenfritt magnesiumsulfat. Lösningsmedlet av- destillerades och den bildade återstoden kromatografe- rades på en kolonn av silikagel, varvid man erhöll 180 mg 7B-(4-amino-3-hydroxiisotiazol-5-yl)tioacetamido-7ß- -metoxi-3-(l-metyltetrazol-5-yl)tiometyl-A3-cefem-4- -karboxylsyra med en blandning av kloroform, metanol, och myrsyra (volymförhâllande 8:2:0,2) såsom eluerings- medel.EXAMPLE 2 -sou conH- ~ “* '___ S 2 ii ä ¿9_ ~ _-N, // -cH2s- N, N o I coon cnš After cooling 40 ml of liquid ammonia to -70 ° C, 183 mg of 4-amino-5-ethylthio-3-hydroxyisothiazole, and then 55 mg of sodium was added to the liquid ammonia. The mixture was stirred for 10 minutes at the same temperature and then liquid ammonia was distilled off. The residue was added with 15 ml of methanol, after which it was cooled to 2 ° C. 15 ml of a methanol solution of 300 mg of 7β-bromoacetamide-7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-33-cephem-4-carboxylic acid were added dropwise to the mixture over a period of 30 seconds, after which stirred for 10 min at the same temperature. The solvent was distilled off under reduced pressure, and after adding 15 ml of water to the residue, the pH of the mixture was adjusted to 2.5 by adding 5% hydrochloric acid. The precipitates formed were extracted with 100 ml of a mixture of n-butanol and ethyl acetate (volume ratio Izl) and the extract was washed with water and then with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue formed was chromatographed on a column of silica gel to give 180 mg of 7B- (4-amino-3-hydroxyisothiazol-5-yl) thioacetamido-7β-methoxy-3- (1-methyltetrazole). -5-yl) thiomethyl-3 3-cephem-4-carboxylic acid with a mixture of chloroform, methanol, and formic acid (8: 2: 0.2 by volume) as eluent.
NMR-spektrun(D6-DMS0) 5 (ppm): 3,36 (3H), 3,54 (2H), 3,58 (2H), 3,94 (za), 4,30 (za), s,o9 (in).NMR Spectrum (D 6 -DMSO) δ (ppm): 3.36 (3H), 3.54 (2H), 3.58 (2H), 3.94 (za), 4.30 (za), s, o9 (in).
EXEMPEL 3 Ho Nncooczns 90115 ' Nïsl songcoNnï--l/ p Of-m / cflgs -ÄIIVN coon cnš Genom att gå tillväga på samma sätt i exempel 2, erhölls 50 mg 76-(4-etoxikarbonylamino-3-hydroxiisotiazol- -5-(yl)tioacetamido-7o-metoxi-3-(l-metyltetrazol-5-yl)tio- 10 15 20 25 30 454 512 17 metyl-A3-cefem-4-karboxylsyra ur 300 mg 4-etoxikarbonyl- -amino-5-etyltio-3-hydroxiisotiazol och 300 mg 7ß-brom- -acetamido-7a~metoxi-3-(1-metyltetrazol-S-yl)tiometyl- -A3-cefemf4-karboxylsyra.EXAMPLE 3 Ho nncooczns 90115 'Nïsl songcoNnï - l / p Of-m / c fl gs -ÄIIVN coon cnš By proceeding in the same manner in Example 2, 50 mg of 76- (yl) thioacetamido-7o-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-A3-cephem-4-carboxylic acid from 300 mg of 4-ethoxycarbonyl-amino-5 -ethylthio-3-hydroxyisothiazole and 300 mg of 7β-bromo-acetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-α3-cephem-4-carboxylic acid.
NMR-spektrum (D6~DMSO) 6 (ppm: 1,14 (311), 3,38 (an), 3,60 (211), 3,81 (za), 3,92 (3H), 4,06 (2H), 4,29 (2H), 5,11 (lH).NMR Spectrum (D 6 -DMSO) δ (ppm: 1.14 (311), 3.38 (an), 3.60 (211), 3.81 (za), 3.92 (3H), 4.06 (2H), 4.29 (2H), 5.11 (1H).
EXEMEL 4 Ho\fi__1I::coNHNn2 Ocnñ S N\S scH2coNH---~T' N--N || H //'""N / CH2S Iiw/N 0' coon CH5 Genom att gå tillväga på samma sätt som i exempel 2, erhölls 100 mg 75-(4-karbazoyl-3-hydroxiisotiazol-5-yl)- tioacetamido-7u-metoxi-3-(1-metyltetrazol-5-yl)tiometyl- -A3-cefem-4-karboxylsyra ur 220 mg 4-karbazoyl-5-etyl- tio-3-hydroxiisotiàzol och 400 mg 7B-bromacetamido-7a- -metoxi-3-(1-metyltetrazol-5-yl)tiometyl-A3-cefem-4- -karboxylsyra.EXAMPLE 4 Ho \ fi__1 I :: coNHNn2 Ocnñ S N \ S scH2coNH --- ~ T 'N - N || H // '"" N / CH 2 S Iiw / N 0' coon CH5 By proceeding in the same manner as in Example 2, 100 mg of 75- (4-carbazoyl-3-hydroxyisothiazol-5-yl) -thioacetamido-7u was obtained -methoxy-3- (1-methyltetrazol-5-yl) thiomethyl- α3-cephem-4-carboxylic acid from 220 mg of 4-carbazoyl-5-ethylthio-3-hydroxyisothiazole and 400 mg of 7B-bromoacetamido-7a- methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-33-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO) ö (ppm): 3,39 (3H), 3,63 (2H), 3,90 (2H), 3,93 (3H), 4,30 (ZH), 5,13 (lfl).NMR Spectrum (D 6 -DMSO) δ (ppm): 3.39 (3H), 3.63 (2H), 3.90 (2H), 3.93 (3H), 4.30 (ZH), δ, 13 (l fl).
EXEMPEL 5 H OOH ' OCH3 | /lL_' _Ä __r”5 N---N /N H5 ___N CH S ,,./2 ”f Coon c 10 15 20 25 30 35 454 512 18 (a) I 60 ml metanol löstes 6,1 g 7ß-bromacetamido- -7a-metoxi-cefalosporansyra_ Därefter tillsattes 15 ml iskyld vattenhaltig lös- ning av 4,3 g trinatriumsalt firflydflmg av44qgb@¿f34gdnmfi- -5-merkaptoisotiazol droppvis till lösningen vid 0-SOC.EXAMPLE 5 H OOH 'OCH3 | / lL_ '_Ä __r ”5 N --- N / N H5 ___N CH S ,,. / 2” f Coon c 10 15 20 25 30 35 454 512 18 (a) In 60 ml of methanol was dissolved 6.1 g of 7ß- bromoacetamido--7a-methoxy-cephalosporanic acid_ Then 15 ml of ice-cold aqueous solution of 4.3 g of trisodium salt fi r fl yd fl mg of 44qgb @ ¿f34gdnm fi- -5-mercaptoisothiazole was added dropwise to the solution at 0-SOC.
Efter omröring av blandningen i 30 min vid samma tempera- tur avdestillerades metanol under förminskat tryck. Åter- stoden blandades med 40 ml vatten, inställes på pH 3 med 2n saltsyra och tvättades med etylacetat. Vattenskiktet inställdes på pH 1 med 2n saltsyra och extraherades 2 ggr med en blandning av n-butanol och etylacetat med volym- förhållandet 1:1. Det organiska skiktet tvättades med en mättad vattenhaltig natriumkloridlösning, torkades över vattenfritt magnesiumsulfat och lösningsmedlet av- destillerades, varvid man erhöll en pulverartad råprodukt.After stirring the mixture for 30 minutes at the same temperature, methanol was distilled off under reduced pressure. The residue was mixed with 40 ml of water, adjusted to pH 3 with 2N hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with 2N hydrochloric acid and extracted twice with a mixture of n-butanol and ethyl acetate in a volume ratio of 1: 1. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain a powdery crude product.
Produkten löstes i en liten mängd metanol och lösningen kyldes med is för bildning av kristaller. Kristallerna utvanns genom filtrering, varvid man fick 4,8 g (64,2 % utbyte) av renade vita kristaller av 7B-(4-karbcxi-3- -hydroxiisotiazol-5-yl)tioacetamid-7a-metoxicefalosporan- syra.The product was dissolved in a small amount of methanol and the solution was cooled with ice to form crystals. The crystals were recovered by filtration to give 4.8 g (64.2% yield) of purified white crystals of 7B- (4-carboxy-3-hydroxyisothiazol-5-yl) thioacetamide-7a-methoxycephalosporanic acid.
NMR-spektrum (D6DMSO): H a (ppm). 5,20 (1H, __š/S , s), .iNx 4,64 (za, /s H , q), ve (k i 4,02 (211, / scnzco- , s), 3,52 (2H, ítcnzo- , q), 9CH3 3,44 (sn, s), 2,04 (3H, -ococH s).NMR Spectrum (D 6 DMSO): H a (ppm). 5.20 (1H, δš / S, s), .iNx 4.64 (za, / s H, q), ve (ki 4.02 (211, / scnzco-, s), 3.52 (2H, itcnzo-, q), 9CH 3 3.44 (sn, s), 2.04 (3H, -ococH s).
UI 10 15 20 30 35 454 512 19 (b) Genom omsättning av 7ß-(4-karboxi~3-hydroxi- tiazol-2-yl)tioacetamido-70-metoxi-cefalosporansyra med 5-merkapto-1-metyltetrazol, erhölls 7B-(4-karboxi- -3-hydroxiisotiazol-5-yl)tioacetamido-7a-metoxi-3- -(1-metyltetrazol-5-yl)tiometyl-A3-cefem-4-karboxyl- syra.(B) By reaction of 7β- (4-carboxy-3-hydroxythiazol-2-yl) thioacetamido-70-methoxy-cephalosporanic acid with 5-mercapto-1-methyltetrazole, 7B was obtained - (4-Carboxy-3-hydroxyisothiazol-5-yl) thioacetamido-7α-methoxy-3- - (1-methyltetrazol-5-yl) thiomethyl-33-cephem-4-carboxylic acid.
På sanna sätt som i exempel l erhölls följande föreningar.In true manner as in Example 1, the following compounds were obtained.
EXEMEL 5 76-(4-cyano-3-hydroxiisotiazol-5-yl)tioacetamido- -7a-metoxi-3-(1-metyltetrazol-5-yl)tiometyl-A3-cefem- -4-karboxylsyra.EXAMPLE 5 76- (4-Cyano-3-hydroxyisothiazol-5-yl) thioacetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-33-cephem-4-carboxylic acid.
NMR-spektrum (D6DMSO): ö (PPm), 3,39 (3H), 3,59 (ZH), 3,92 (3H), 4,11 (ZH), 4,28 (2H), 5,10 (lH).NMR Spectrum (D 6 DMSO): δ (PPm), 3.39 (3H), 3.59 (ZH), 3.92 (3H), 4.11 (ZH), 4.28 (2H), 5.10 (1H).
EXEMEL 7 7B-(3-hydrøxí-4-fenylisotiazol-5-yl)tioacetamido- -7a-metoxi-3-(1-metyltetrazol-5-yl)tiometyl-A3-cefem-4- -karboxylsyra.EXAMPLE 7 7B- (3-Hydroxy-4-phenylisothiazol-5-yl) thioacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-33-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO): ö (ppmn 3,40 (BH), 3,56 (zH), 3,87 (zn), 3,92 (3H), 4,27 (ZH), 5,05 (lH).NMR Spectrum (D6-DMSO): δ (ppmn 3.40 (BH), 3.56 (zH), 3.87 (zn), 3.92 (3H), 4.27 (ZH), 5.05 (1H).
EXEMPEL 8 7B-(3-amino-4-cyanoisotiazol-5-yl)tioacetamido-7a- -metoxi-3-(l-metyltetrazol-5-yl)tiometyl-A3-cefem-4- -karboxylsyra.EXAMPLE 8 7B- (3-Amino-4-cyanoisothiazol-5-yl) thioacetamido-7α- -methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-A3-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMS0): 5 (ppmn 3,40 (321), 3,60 (zH), 3,95 (3H), 4,08 (zfl), 4,31 (2H), 5,11 (lH).NMR Spectrum (D 6 -DMSO): δ (ppmn 3.40 (321), 3.60 (zH), 3.95 (3H), 4.08 (z fl), 4.31 (2H), 5.11 (1H).
EXEMPEL 9 7B~(3~dimetylkarbamoyl-3-hydroxiisotiazol-5-yl)- tioacetamido-7a-metoxi-3-(1-metyltetrazol-5-yl)tio- metyl-A3-cefem-4-karboxylsyra.EXAMPLE 9 7B- (3-Dimethylcarbamoyl-3-hydroxyisothiazol-5-yl) -thioacetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-A3-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO) 6 (ppm): 2,88 (6H), 3,38 (3H), 3,56 4,26 (za), 5,04 (111).NMR Spectrum (D 6 -DMSO) δ (ppm): 2.88 (6H), 3.38 (3H), 3.56 4.26 (za), 5.04 (111).
(ZH), 3,90 (SH), 10 15 20 25 30 35 454 512 20 EXEMPEL 10 ' i 76-(3-hydroxiisotiazol-4-yl)tioacetamido-7a-metoxi~ f U -3-(l-metyltetrazol-S-yl)tiometyl-A3-cefem-4-karboxyl- syra.(ZH), 3.90 (SH), EXAMPLE 10 'in 76- (3-hydroxyisothiazol-4-yl) thioacetamido-7α-methoxy- [3- (1-methyltetrazole) -S-yl) thiomethyl-33-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMS0) 6 (ppm}: 3,39 (3H), 3,48 (2H), 3,66 (2H), 3,94 (3H), 4,26 (ZH), 5,11 (lH), 7,59 (lH).NMR Spectrum (D 6 -DMSO) δ (ppm}: 3.39 (3H), 3.48 (2H), 3.66 (2H), 3.94 (3H), 4.26 (ZH), δ, 11 (1H), 7.59 (1H).
EXEMPEL ll 7B-(4-cyano-2-metyl-3-oxo-2,3-dihydroisotiazol-5- -yl)tioacetamido-7afmetoxi-3-(l-metyltetrazol-5-yl)- tiometyl-A3-cefem-4-karboxylsyra.EXAMPLE 11 7B- (4-Cyano-2-methyl-3-oxo-2,3-dihydroisothiazol-5-yl) thioacetamido-7-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-33-cephem 4-carboxylic acid.
NMR-spektrum (D6-DMSO) ö (ppm): 3,40 (3H), 3,@4 (2H), 3,92 (8H), 4,30 (ZH), 5,16 (IH).NMR Spectrum (D 6 -DMSO) δ (ppm): 3.40 (3H), 3. @ 4 (2H), 3.92 (8H), 4.30 (ZH), 5.16 (1H).
EXEMPEL 12 7ß-[4-cyano-2-(2-hydroxietyl)-3-oxo-2,3-dihydro~ isotiazol-5-yl]tioacetamido-7ufmetoxi-3-(l-metyltetrazol- -5-yl)tiometyl-A3-cefem-4-karboxylsyra.EXAMPLE 12 7β- [4-Cyano-2- (2-hydroxyethyl) -3-oxo-2,3-dihydroisothiazol-5-yl] thioacetamido-7-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl -A3-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO) ö (ppm): 3,40 (3H), 3,5-3,6 (3H), 3,76 (2H), 3,93 (3H), 4,16 (ZH), 4,32 (ZH), 5,14 (lH).NMR Spectrum (D6-DMSO) δ (ppm): 3.40 (3H), 3.5-3.6 (3H), 3.76 (2H), 3.93 (3H), 4.16 (ZH ), 4.32 (ZH), 5.14 (1H).
EXEMPEL 13 75-(4-karbamoyl-3-hydroxiisotiazol-5-yl)tioacetamido- -7a-metoxi-3-(l-metyltetrazol-5-yl)tiomety1-A3-cefem- -4-karboxylsyra.EXAMPLE 13 75- (4-Carbamoyl-3-hydroxyisothiazol-5-yl) thioacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-A3-cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO) ö (ppm): 3,39 (3H), 3,49 (2H), 3,64 (2H), 3,93 (3H), 4,28 (2H), 5,07 (lH).NMR Spectrum (D 6 -DMSO) δ (ppm): 3.39 (3H), 3.49 (2H), 3.64 (2H), 3.93 (3H), 4.28 (2H), δ, 07 (1H).
EXEMPEL 14 7B-(3-hydroxi-4-hydroximetylisotiazol-5-yl)tio~ acetamido-7afmetoxi-3-(l-metyltetrazol-5-yl)tiometyl- -A3-cefem-4-karboxylsyra.EXAMPLE 14 7B- (3-Hydroxy-4-hydroxymethylisothiazol-5-yl) thioacetamido-7-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-α-Cephem-4-carboxylic acid.
NMR-spektrum (D6-DMSO) ö (ppm): 3,40 (3H), 3,58 (2H), 3,83 (2H), 4,12 (2H), 4,30 (ZH), 5,10 (lH).NMR Spectrum (D 6 -DMSO) δ (ppm): 3.40 (3H), 3.58 (2H), 3.83 (2H), 4.12 (2H), 4.30 (ZH), δ, 10 (1H).
IW 3,92 (3H), 10 15 20 25 30 35 454 512 21 EXEMPEL 15 I 7 ml metylenklorid löstes 300 mg 7B-amino-7a- -metoxi-3-(l-metyltetrazol-5-yl)tiometyl-A3-cefem-4- -karboxylsyrabenshydrylester, som kylts till -30°C och 460 mg pyridin tillsattes. Separat framställdes en syrakloridlösning av en suspension av 240 mg kalium- -(4-cyano-3-metoxiisotiazol-5-yl)tioacetat i 10 ml metylenklorid, 170 mg oxalylklorid och en droppe dimetylformamid. Syrakloridlösningen tillsattes dropp- vis till den angivna lösningen vid -30°C till -20°C och det hela omröres i l h vid samma temperatur. Reak- tionsblandningen försattes med 30 ml kloroform och tvättades 2 ggr med 2 %-ig saltsyra och 2 ggr med.mäüzm natriumvätekarbonat, det organiska skiktet avskildes och torkades över vattenfritt magnesiumsul- fat. Det organiska skiktet kondenserades under för- minskat tryck och återstoden kromatograferades på kolonn med silikagel med etyleringsmedel av en blandning av kloroform och isopropanol (volymförhållande 10:l) och man erhöll l9O mg 76-(4-cyano-3-metoxi-isotiazol-5- -yl)tioacetamido~7a-metoxi-3-(1-metyltetrazol-5-yl)tio- metyl-A3-cefem-4-karboxylsyrabenshydrylester.IW 3.92 (3H), EXAMPLE 15 300 ml of 7B-amino-7α- -methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-A3- were dissolved in 7 ml of methylene chloride. cephem-4-carboxylic acid benzhydryl ester, which was cooled to -30 ° C and 460 mg of pyridine was added. Separately, an acid chloride solution was prepared from a suspension of 240 mg of potassium - (4-cyano-3-methoxyisothiazol-5-yl) thioacetate in 10 ml of methylene chloride, 170 mg of oxalyl chloride and one drop of dimethylformamide. The acid chloride solution was added dropwise to the indicated solution at -30 ° C to -20 ° C and the whole was stirred for 1 hour at the same temperature. The reaction mixture was added with 30 ml of chloroform and washed twice with 2% hydrochloric acid and twice with sodium bicarbonate, the organic layer was separated and dried over anhydrous magnesium sulphate. The organic layer was condensed under reduced pressure and the residue was chromatographed on a silica gel column with ethylating agent of a mixture of chloroform and isopropanol (10: 1 by volume) to give 120 mg of 76- (4-cyano-3-methoxy-isothiazole-5). - -yl) thioacetamido-7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-A3-cephem-4-carboxylic acid benzhydryl ester.
I 2 ml metylenklorid löstes den angivna produkten och en blandning av 1,6 ml trifluorättiksyra och anisol (volymförhållande: 3=1) tillsattes aroppvis vid -15°c till -SCC och det hela omrördes i 40 min vid samma temperatur, varefter lösningsmedlet avdestillerades under förminskat tryck, återstoden triturerades med 10 ml eter, tryck, varvid man fick l2O mg av ett pulver av 7ß-(4- filtrerades och torkades under förminskat -cyano-3-metoxiisotiazol-5-yl)tioacetamido-7a-metoxi- -3-(l-metyltetrazol-5-yl)tiometyl-A3~cefem-4-karboxyl- syra.In 2 ml of methylene chloride the indicated product was dissolved and a mixture of 1.6 ml of trifluoroacetic acid and anisole (volume ratio: 3 = 1) was added stepwise at -15 ° C to -SCC and the whole was stirred for 40 minutes at the same temperature, after which the solvent was distilled off. under reduced pressure, the residue was triturated with 10 ml of ether, pressure to give 120 mg of a powder of 7β- (4-filtered and dried under reduced -cyano-3-methoxyisothiazol-5-yl) thioacetamido-7α-methoxy- 3- (1-methyltetrazol-5-yl) thiomethyl-A3-cephem-4-carboxylic acid.
NMR-spektrum (DGDMSO) 5 (ppm): 3,40 (3H), 3,58 (2H), 3,92 (3H), 3,99 4,15 (2H), 4,18 (ZH), 5,12 (lH). (3H),NMR Spectrum (DGDMSO) δ (ppm): 3.40 (3H), 3.58 (2H), 3.92 (3H), 3.99 4.15 (2H), 4.18 (ZH), δ 12 (1H). (3H),
Claims (2)
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JP52068699A JPS5854157B2 (en) | 1977-06-10 | 1977-06-10 | New derivatives of cephalosporin compounds and their production method |
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JP (1) | JPS5854157B2 (en) |
AU (1) | AU518620B2 (en) |
BE (1) | BE867994A (en) |
DE (1) | DE2857816C2 (en) |
FR (1) | FR2405953A1 (en) |
GB (1) | GB1604740A (en) |
HU (1) | HU184788B (en) |
SE (1) | SE454512B (en) |
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EP0187355A1 (en) | 1981-09-23 | 1986-07-16 | E.R. Squibb & Sons, Inc. | Process for preparing beta-lactam antibiotics |
ZA874696B (en) | 1986-07-03 | 1988-01-04 | F. Hoffmann-La Roche & Co. Aktiengesellschaft | Acyl derivatives |
PT620225E (en) | 1993-04-16 | 2003-03-31 | Basilea Pharmaceutica Ag | DERIVATIVES OF CEFALOSPORINA |
US5811419A (en) * | 1996-01-16 | 1998-09-22 | Hoffmann-La Roche Inc. | Isooxacephem-derivatives |
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IL29235A (en) * | 1967-01-05 | 1971-10-20 | Bristol Myers Co | 7-(pyridylthioacetamido)cephalosporanic acid derivatives and their preparation |
JPS5165789A (en) * | 1974-11-30 | 1976-06-07 | Sankyo Co | 77 metokishisefuarosuhorinkagobutsuno seiho |
CA1088049A (en) * | 1975-06-03 | 1980-10-21 | Takashi Masugi | 3-substituted-7-substituted alkanamido-3-cephem-4- carboxylic acid compounds and processes for preparation thereof |
DE2539214C2 (en) * | 1975-09-03 | 1984-03-29 | E.R. Squibb & Sons, Inc., 08540 Princeton, N.J. | 7-methoxythienyl-ureido-cephalosporin and medicinal product containing it |
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1977
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1978
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1979
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1980
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DE2857816C2 (en) | 1985-05-09 |
SU843752A3 (en) | 1981-06-30 |
UA5922A1 (en) | 1994-12-29 |
JPS5854157B2 (en) | 1983-12-02 |
FR2405953B1 (en) | 1983-07-18 |
SE8306298L (en) | 1983-11-16 |
AU518620B2 (en) | 1981-10-08 |
JPS543090A (en) | 1979-01-11 |
UA5924A1 (en) | 1994-12-29 |
SU904525A3 (en) | 1982-02-07 |
HU184788B (en) | 1984-10-29 |
AU3698878A (en) | 1979-12-13 |
BE867994A (en) | 1978-12-11 |
GB1604740A (en) | 1981-12-16 |
SE8306298D0 (en) | 1983-11-16 |
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